Novel anthranilic acid derivatives

ABSTRACT

The invention is concerned with novel anthranilic acid derivatives of formula (I)  
                 
 
wherein R 1  to R 14  and n are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds are HM74A agonists and can be used as medicaments.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No.05105176.1, filed Jun. 14, 2005, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention is directed to novel anthranilic acid derivatives of theformula (I)

and pharmaceutically acceptable salts and pharmaceutically acceptableesters thereof.

Further, the invention is directed to a process for the manufacture ofthe above compounds, pharmaceutical preparations which contain suchcompounds as well as the use of these compounds for the production ofpharmaceutical preparations.

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND

Coronary heart disease (CHD) remains the leading cause of death inWestern countries. In the United States 13.2 million or 4.85% of thepopulation is affected, with 1.2 million new or recurrent attacks andaround 500 thousand deaths per year (American Heart Association,Statistics for 2001). The disease is influenced by severalwell-established risk factors, such as age, sex, blood lipids, bloodpressure, smoking, diabetes, and body mass index (BMI) as an indicatorof overweight and obesity. The National Cholesterol Education Program(NCEP) Adult Treatment Panel III defines elevated plasma levels of lowdensity lipoprotein (LDL) cholesterol (LDL-C≧160 mg/dL), and low levelsof high density lipoprotein (HDL) cholesterol (HDL-C≦40 mg/dL) asindependent risk factors for CHD. Many prospective epidemiologicalstudies have indicated that a decreased HDL-C level is a significantindependent risk factor for heart disease, while increased HDL-Clevels≧60 mg/dL (≧1.55 mmol) have a protective role against CHD.

Nicotinic acid (Niacin), a vitamin of the B complex, is used for almost40 years as a lipid-lowering drug with a favorable profile for alllipoprotein classes. Numerous clinical studies have shown the beneficialeffects of niacin, demonstrating a reduction of coronary artery diseaseand overall mortality. Niacin is the most potent agent currentlyavailable to raise HDL. It has been proposed than niacin's main mode ofaction is through inhibition of lipolysis in the adipose tissue havingas a result the reduction of free fatty acids (FFA) in plasma and liverand consequently the decreased production of very low densitylipoproteins (VLDL), accounting for the reduction of total cholesterol(TC), triglycerides (TGs), and LDL-C. Due to the decreased TG richlipoproteins levels, less modification of HDL particles occurs upon theaction of cholesteryl ester transfer protein (CETP), resulting in adecreased catabolism of HDL. A direct inhibition of lipoprotein AI-HDL(LPAI-HDL) particle uptake by the liver has been also proposed,accounting for the overall HDL raising properties of niacin (Jin et alArterioscler. Thromb. Vasc. Biol. 1997, 17, 2020-2028).

Niacin also has anti-diabetic, anti-thrombotic and anti-inflammatoryproperties that contribute to the overall cardioprotective effects.Through a variety of mechanisms niacin reduces thrombosis, such as thereduction of lipoprotein (a) (Lp(a)) which is a potent inhibitor offibrinolytic activity, and it is the only currently approved drug thateffectively reduces the serum levels of Lp(a) (Carlson et al J InternMed 1989, 17, 2020-8). Inflammation is a critical component ofatherosclerosis, leading to recruitment of macrophages which bothpromote plaque development and decrease plaque stability thus increasingcardiovascular risk. Niacin has been suggested to have anti-inflammatoryproperties, such as the reduction of C-reactive protein (CRP) levels(Grundy et al Arch Intern Med 2002, 162, 1568-76). Several prospectivestudies have established a strong and direct correlation betweencardiovascular risk and CRP levels, a measure of vascular inflammation.Extensive use of niacin has been hampered due to side effects, mainlyintense cutaneous flushing.

Recently HM74A/HM74, a G-protein coupled receptor (GPCR), was identifiedas a receptor for niacin and proposed as the mediator of the niacineffects (Wise et. al. J Biol Chem. 2003, 278 (11) 9869-9874 and Soga etal Biochem Biophys Res Commun 2003 303 (1) 364-369). In support,deletion of the PUMA-G (HM74A orthologue) in mice abrogated the niacineffects on reduction of plasma free fatty acids and triglycerides(Tunaru et al Nature Medicine 2003, (3) 352-255).

Thus, a need exists for compounds selective for HM74A for the treatmentand/or prevention of diseases modulated by HM74A agonists.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, provided is a compound offormula (I):

wherein

-   R¹ is hydrogen or lower-alkyl;-   R², R³, R⁴ and R⁵, independently from each other, are hydrogen,    halogen, lower-alkyl or fluoro-lower-alkyl, with the proviso that R⁴    is not bromine;-   R⁶, R⁷, R⁸ and R⁹, independently from each other, are hydrogen,    lower-alkyl, lower-alkoxy, cycloalkyl, halogen,    lower-alkoxy-lower-alkyl, fluoro-lower-alkyl, fluoro-lower-alkoxy,    lower alkenyl, lower alkinyl or cyano;-   R¹⁰, R¹¹R¹² and R¹³ independently from each other are hydrogen,    lower-alkyl or fluoro-lower-alkyl, or R¹⁰ and R¹¹ are bound together    to form a cycloalkyl together with the carbon atom to which they are    attached and —R¹⁰—R¹¹— is —(CH₂)₂₋₆—, or R¹² and R¹³ are bound    together to form a cycloalkyl together with the carbon atom to which    they are attached and —R¹²—R¹³— is —(CH₂)₂₋₆—;-   R¹⁴ is phenyl or heteroaryl, which phenyl or heteroaryl is    optionally substituted with 1 to 3 substituents selected from the    group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl,    lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,    lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,    R¹⁵R¹⁶NC(O), R¹⁵R¹⁶NC(O)-lower-alkyl, fluoro-lower-alkyl,    R¹⁵R¹⁶N-lower-alkyl, R¹⁵R¹⁶N, lower-alkyl-SO₂, lower-alkyl-SO₂O,    lower-alkyl-SO₂—NR¹⁵, R¹⁵R¹⁶NSO₂, cyano, heteroaryl, cycloalkyl,    lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl,    fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl;-   R¹⁵ and R¹⁶ independently from each other are hydrogen or    lower-alkyl;-   m is 0 or 1;-   n is 0 or 1;-   and pharmaceutically acceptable salts and pharmaceutically    acceptable esters thereof;-   with the proviso that the compound of formula (I) is not selected    from the group consisting of:-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester.

In another embodiment of the present invention, provided is a processfor the manufacture of compounds of formula (I), which process comprises

-   reacting a compound of formula (II)    with a compound of formula (III),    wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,    m and n are as defined above and R¹⁷ is OH, Cl, Br, or a carboxylic    acid moiety to form an anhydride;-   or-   hydrolysis of a compound of formula (Ia)    wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, m    and n are as defined above and R¹ is lower-alkyl.

In a further embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effecitveamount of a compound according to formula (I) or a compound selectedfrom the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-F[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,-   and a pharmaceutically acceptable carrier and/or adjuvant.

In a yet another embodiment of the present invention, provided is amethod for the treatment and/or prevention of diseases which aremodulated by HM74A agonists, comprising the step of administering atherapeutically effective amount of a compound according to formula (I)or a compound selected from the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,-   to a human being or animal in need thereof.

DETAILED DESCRIPTION

The novel compounds of the present invention exceed the compounds knownin the art, inasmuch as they bind to and activate HM74A. The compoundsof the present invention are selective for HM74A by which is meant thatthey show greater affinity for HM74A than for HM74. The compounds of thepresent invention are expected to have an enhanced therapeutic potentialand exhibit reduced side effects compared to nicotinic acid. Thecompounds of the present invention can be used as medicaments for thetreatment and/or prevention of diseases which are modulated by HM74Aagonists. Examples of such diseases are increased lipid and cholesterollevels, particularly dyslipidemia, low HDL-cholesterol, atheroscleroticdiseases, hypertriglyceridemia, thrombosis, angina pectoris, peripheralvascular disease, stroke, diabetes, particularly non-insulin dependentdiabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson'sdisease, schizophrenia, sepsis, inflammatory diseases (such as e.g.colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseasesthat have an inflammatory component such as e.g. Alzheimer's disease orimpaired/improvable cognitive function).

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms. Lower-alkyl groups asdescribed below also are preferred alkyl groups.

The term “lower-alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto seven carbon atoms, preferably one to four carbon atoms. This term isfurther exemplified by such radicals as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, t-butyl and the like. Lower-alkyl groupscan optionally be substituted, e.g. by hydroxy or cyano. Suchsubstituted lower-alkyl-groups are referred to as “hydroxy-lower-alkyl”or “cyano-lower-alkyl”. Unsubstituted lower-alkyl groups are preferred

The term “fluoro-lower-alkyl” refers to lower-alkyl groups which aremono- or multiply substituted with fluorine. Examples offluoro-lower-alkyl groups are e.g. CFH₂, CF₂H, CF₃, CF₃CH₂, CF₃(CH₂)₂,(CF₃)₂CH and CF₂H—CF₂.

The term “alkenyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising anolefinic bond and up to 20, preferably up to 16 carbon atoms. The term“lower-alkenyl” refers to a straight-chain or branched hydrocarbonresidue comprising an olefinic bond and up to 7, preferably up to 4carbon atoms, such as e.g. 2-propenyl.

The term “alkinyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising a triplebond and up to 20, preferably up to 16 carbon atoms. The term“lower-alkinyl” refers to a straight-chain or branched hydrocarbonresidue comprising a triple bond and up to 7, preferably up to 4 carbonatoms, such as e.g. 2-propinyl.

The term “amino”, alone or in combination, signifies a primary,secondary or tertiary amino group bonded via the nitrogen atom, with thesecondary amino group carrying an alkyl or cycloalkyl substituent andthe tertiary amino group carrying two similar or different alkyl orcycloalkyl substituents or the two nitrogen substitutents togetherforming a ring, such as, for example, —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl orpiperidino etc., preferably primary amino, dimethylamino anddiethylamino and particularly dimethylamino.

The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl.

The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ is alower-alkyl.

The term “fluoro-lower-alkoxy” refers to the group R″—O—, wherein R″ isfluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are e.g.CFH₂—O, CF₂H—O, CF₃—O, CF₃CH₂—O, CF₃(CH₂)₂—O, (CF₃)₂CH—O, andCF₂H—CF₂—O.

The term “aryl”, alone or in combination, relates to the phenyl ornaphthyl group, preferably the phenyl group, which can optionally besubstituted by 1 to 5, preferably 1 to 3, substituents independentlyselected from the group consisting of halogen, lower-alkyl,hydroxy-lower-alkyl, lower-alkoxy, carboxy, carboxy-lower-alkyl,lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl, H₂NC(O),(H,lower-alkyl)NC(O), (lower-alkyl)₂NC(O), H₂NC(O)-lower-alkyl,(H,lower-alkyl)NC(O)-lower-alkyl, (lower-alkyl)₂NC(O)-lower-alkyl,fluoro-lower-alkyl, H₂N-lower-alkyl, (H,lower-alkyl)N-lower-alkyl,(lower-alkyl)₂N-lower-alkyl, lower-alkyl-SO₂, lower-alkyl-SO₂O,lower-alkyl-SO₂—NH lower-alkyl-SO₂—N(lower-alkyl), H₂NSO₂,(H,lower-alkyl)NSO₂, (lower-alkyl)₂NSO₂, cyano, heteroaryl, cycloalkyl,lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl,fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl. Other possiblesubstituents are e.g. hydroxy, amino, NO₂, dioxo-lower-alkylene (forminge.g. a benzodioxyl group), lower-alkylcarbonyl, lower-alkylcarbonyloxy,lower-alkylcarbonyl-NH, cycloalkyl, phenyl and phenyloxy. Preferredsubstituents are halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxyand fluoro-lower-alkoxy. Furthermore, aryl groups can be substituted asdescribed in the description below.

The term “heteroaryl” refers to an aromatic 5 to 6 membered monocyclicring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3atoms selected from nitrogen, oxygen and/or sulphur, such as furyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl,oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,benzoimidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzoxazolyl,benzoisoxazolyl and quinolinyl. Preferred heteroaryl groups arepyridinyl and quinolinyl. A heteroaryl group may be unsubstituted oroptionally have a substitution pattern as described earlier inconnection with the term “aryl”. Furthermore, a heteroaryl group may besubstituted as described in the specification below and in the claims.

The term “protecting group” (PG) refers to groups such as e.g. acyl,alkoxycarbonyl, aryloxycarbonyl, silyl, or imine-derivatives, which areused to temporarily block the reactivity of functional groups. Wellknown protecting groups are e.g. t-butyloxycarbonyl, benzyloxycarbonyl,fluorenylmethyloxycarbonyl or diphenylmethylene which can be used forthe protection of amino groups, or lower-alkyl-, β-trimethylsilylethyl-and β-trichloroethyl-esters, which can be used for the protection ofcarboxy groups.

The term “pharmaceutically acceptable esters” embraces derivatives ofthe compounds of formula (I), in which a carboxy group has beenconverted to an ester. Lower-alkyl, hydroxy-lower-alkyl,lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- ordi-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl,pyrrolidino-lower-alkyl, piperidino-lower-alkyl, piperazino-lower-alkyl,lower-alkyl-piperazino-lower-alkyl and aralkyl esters are examples ofsuitable esters. The methyl, ethyl, propyl, butyl and benzyl esters arepreferred esters. The methyl and ethyl esters are especially preferred.The term “pharmaceutically acceptable esters” furthermore embracescompounds of formula (I) in which hydroxy groups have been converted tothe corresponding esters with inorganic or organic acids such as, nitricacid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms.

Compounds of formula (I) in which a COOH group is present can form saltswith bases. Examples of such salts are alkaline, earth-alkaline andammonium salts such as e.g. Na—, K—, Ca—, Mg— andtrimethylammonium-salt. The compounds of formula (I) can also besolvated, e.g. hydrated. The solvation can be effected in the course ofthe manufacturing process or can take place e.g. as a consequence ofhygroscopic properties of an initially anhydrous compound of formula (I)(hydration). The term pharmaceutically acceptable salts also includespharmaceutically acceptable solvates.

In detail, the present invention relates to compounds of formula (I)

wherein

-   R¹ is hydrogen or lower-alkyl;-   R², R³, R⁴ and R⁵, independently from each other, are hydrogen,    halogen, lower-alkyl or fluoro-lower-alkyl, with the proviso that R⁴    is not bromine;-   R⁶, R⁷, R⁸ and R⁹, independently from each other, are hydrogen,    lower-alkyl, lower-alkoxy, cycloalkyl, halogen,    lower-alkoxy-lower-alkyl, fluoro-lower-alkyl, fluoro-lower-alkoxy,    lower alkenyl, lower alkinyl or cyano;-   R¹⁰, R¹¹, R¹² and R¹³ independently from each other are hydrogen,    lower-alkyl or fluoro-lower-alkyl, or R¹⁰ and R¹¹ are bound together    to form a cycloalkyl together with the carbon atom to which they are    attached and —R¹⁰—R¹¹— is —(CH₂)₂₋₆—, or R¹² and R¹³ are bound    together to form a cycloalkyl together with the carbon atom to which    they are attached and —R¹²—R¹³— is —(CH₂)₂₋₆—;-   R¹⁴ is phenyl or heteroaryl, which phenyl or heteroaryl is    optionally substituted with 1 to 3 substituents selected from the    group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl,    lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,    lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,    R¹⁵R¹⁶NC(O), R¹⁵R¹⁶NC(O)-lower-alkyl, fluoro-lower-alkyl,    R¹⁵R¹⁶N-lower-alkyl, R¹⁵R¹⁶N,lower-alkyl-SO₂, lower-alkyl-SO₂O,    lower-alkyl-SO₂—NR¹⁵, R¹⁵R¹⁶NSO₂, cyano, heteroaryl, cycloalkyl,    lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl,    fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl;-   R¹⁵ and R¹⁶ independently from each other are hydrogen or    lower-alkyl;-   m is 0 or 1;-   n is 0 or 1;-   and pharmaceutically acceptable salts and pharmaceutically    acceptable esters thereof;-   with the proviso that the compound of formula (I) is not selected    from the group consisting of:-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester.

Compounds of formula (I) are individually preferred and physiologicallyacceptable salts thereof are individually preferred and pharmaceuticallyacceptable esters thereof are individually preferred, with the compoundsof formula (I) being particularly preferred.

The compounds of formula (I) can have one or more asymmetric C atoms andcan therefore exist as an enantiomeric mixture, diastereomeric mixtureor as optically pure compounds.

Preferred compounds of formula (I) as described above are those, whereinR¹ is hydrogen. In compounds wherein R¹ is lower-alkyl, R¹ preferably isC₂₋₇-alkyl. Other preferred compounds of formula (I) as described aboveare those wherein R², R³, R⁴ and R⁵, independently from each other, arehydrogen, halogen or fluoro-lower-alkyl, with the proviso that R⁴ is notbromine. Preferably R², R³, R⁴ and R⁵, independently from each other,are hydrogen or halogen, with the proviso that R⁴ is not bromine.Preferably, R² is hydrogen or fluorine. Other preferred compounds arethose, wherein R³ is hydrogen. Still other preferred compounds arethose, wherein R⁴ is hydrogen or fluorine. Compounds, wherein R⁵ ishydrogen are also preferred.

Another preferred embodiment of the present invention relates tocompounds of formula (I) as defined above, wherein R⁶, R⁷, R⁸ and R⁹,independently from each other, are hydrogen, lower-alkyl orlower-alkoxy. In such compounds, R⁶ preferably is hydrogen, methyl ormethoxy. Other preferred compounds are those, wherein R⁷ is hydrogen ormethyl. Compounds wherein R⁸ is hydrogen are also preferred. Furtherpreferred compounds are those, wherein R⁹ is hydrogen.

Another preferred embodiment of the present invention refers tocompounds of formula (I) as described above, wherein R¹⁴ is pyridinyl,quinolinyl or phenyl which is optionally substituted with 1 to 3substituents selected from the group consisting of halogen, lower-alkyl,lower-alkoxy, lower-alkyl-SO₂, lower-alkoxy-carbonyl, cyano,fluoro-lower-alkyl, R¹⁵R¹⁶NC(O) and triazolyl, wherein R¹⁵ and R¹⁶independently from each other are hydrogen or lower-alkyl. Among thesecompounds, those ae particularly preferred, wherein R¹⁴ is phenyl,2-methyl-phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 3-fluoro-phenyl,3-methyl-phenyl, quinolin-8-yl, 4-[1,2,4]-triazol-1-yl-phenyl,2,4-difluoro-phenyl, pyridin-2-yl or 2,5-difluoro-phenyl.

In other preferred compounds of the present invention m is 0. Compounds,wherein n is 0 or 1 and R¹² and R¹³ are hydrogen are also preferred,particularly those, wherein n is 0.

In particular, preferred compounds are the compounds of formula (I)described in the examples as individual compounds as well aspharmaceutically acceptable salts as well as pharmaceutically acceptableesters thereof.

Preferred compounds of formula (I) are those selected from the groupconsisting of:

-   2-(4-Benzyloxy-benzoylamino)-benzoic acid,-   2-[4-(4-Fluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(3,4-Dichloro-phenoxy)-benzoylamino]-benzoic acid,-   2-(4-p-Tolyloxy-benzoylamino)-benzoic acid,-   2-[4-(3-Methoxy-phenoxy)-benzoylamino]-benzoic acid,-   2-(4-o-Tolyloxy-benzoylamino)-benzoic acid,-   2-[4-(4-Methoxy-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(4-Chloro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(3,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(4-Methanesulfonyl-phenoxy)-benzoylamino]-benzoic acid,-   2-{4-[4-Methoxycarbonyl)phenoxy]benzoyl}aminobenzoic acid,-   2-[4-(3,5-Dichloro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(4-Cyano-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(3-Chloro-phenoxy)-benzoylamino]-benzoic acid,-   2-(4-m-Tolyloxy-benzoylamino)-benzoic acid,-   2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoic acid,-   2-[4-(4-Trifluoromethyl-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(4-Carbamoyl-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(4-Dimethylaminomethyl-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoic acid,-   2-[4-(Pyridin-3-yloxy)-benzoylamino]-benzoic acid,-   2-[4-(3,4-Dimethyl-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(2,3-Difluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid,-   2-(2-Methyl-4-phenoxy-benzoylamino)-benzoic acid,-   2-(2-Methoxy-4-phenoxy-benzoylamino)-benzoic acid,-   5-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid,-   4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and-   2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid,-   and pharmaceutically acceptable salts and esters thereof.

Particularly preferred compounds of formula (I) are those selected fromthe group consisting of

-   2-(4-o-Tolyloxy-benzoylamino)-benzoic acid,-   2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-(4-m-Tolyloxy-benzoylamino)-benzoic acid,-   2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoic acid,-   2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoic acid,-   2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid,-   2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid,-   4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and-   2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid-   and pharmaceutically acceptable salts and esters thereof.

Other preferred compounds as defined above are those selected from thegroup consisting of

-   2-[4-(3-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,-   2-[4-(2-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,-   2-[4-(2,4-Difluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,-   4-Chloro-5-fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and-   2-(4-Phenoxy-benzoylamino)-5-trifluoromethyl-benzoic acid,-   and pharmaceutically acceptable salts and esters thereof.

It will be appreciated that the compounds of general formula (I) in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

The invention further relates to a process for the manufacture ofcompounds of formula (I) as defined above, which process comprises

-   reacting a compound of formula (II)    with a compound of formula (III),    wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,    m and n are as defined above and R¹⁷ is OH, Cl, Br, or a carboxylic    acid moiety to form an anhydride;-   or-   hydrolysis of a compound of formula (Ia)    wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, m    and n are as defined above and R¹ is lower-alkyl.

If R¹⁷ is a carboxylic acid moiety, it is preferably pivaloylic acid,p-nitrobenzoic acid, p-trifluoromethylbenzoic acid, 2,4,6-trichlorobenzoic acid, acetic acid, trifluoroacetic acid, carbonic acidmonoisobutyl ester, diphenyl phosphinic acid or benzene sulfonic acid toform an asymmetric anhydride, or it is the remainder of a second moietyof formula (III) bound via an oxygen atom to form a symmetric anhydride.Preferably, R¹⁷ is Cl.

The reaction of a compound of formula (II) with a compound of formula(III) or the reaction of a compound of formula (Ia) can be performedunder reaction conditions well known to the person skilled in the art.Such reactions can conveniently be carried out for amide bond formation(process a)) with compounds of formula (III) (R¹⁷═Cl, Br) or with mixedor symmetric anhydrides (III), wherein R¹⁷ is a carboxylic acid moietysuch as e.g. pivaloylic acid, p-nitrobenzoic acid,p-trifluoromethylbenzoic acid, 2,4,6-trichloro benzoic acid, aceticacid, trifluoroacetic acid, carbonic acid monoisobutyl ester, diphenylphosphinic acid or benzene sulfonic acid or the remainder of a secondmoiety of formula (III) bound via an oxygen atom to form a symmetricanhydride, in a solvent such as dichloromethane, in the presence of abase such as triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholineat temperatures between 0° C. and ambient temperature, with compounds offormula (III) (R¹⁷═OH) in the presence ofN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride or BOP(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate)in the presence of a base such as ethyl-diisopropyl-amine,triethylamine, N-methylmorpholine optionally in the presence of4-dimethylamino-pyridine or HOBt (1-hydroxybenzo-triazole) in solventssuch as dichloromethane, DMF, DMA or dioxane at temperatures between 0°C. and ambient temperature or for process (b) by treatment with analkali hydroxide like LiOH or NaOH in a polar solvent such astetrahydrofuran, methanol, ethanol or water or mixtures thereof. If oneof the starting materials II, III or Ia contains one or more functionalgroups which are not stable or are reactive under the reactionconditions, appropriate protecting groups (as described e.g. in“Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M.Wutts, 2^(nd) Ed., 1991, Wiley N.Y.) can be introduced before thecondensation step applying methods well known in the art. Suchprotecting groups can be removed at a later stage of the synthesis usingstandard methods described in the literature.

The present invention also relates to compounds of formula (I) asdefined above, when prepared by a process as described above.

The compounds of formula (I) can be prepared by methods known in the artor as described below in schemes 1 to 4. All starting materials areeither commercially available, described in the literature or can beprepared by methods well known in the art. Unless otherwise indicated,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, m and n areas described above

The preparation of compounds of formula (I) is described in scheme 1.Starting anilines II and carboxylic acids III (R⁷═OH), carboxylic acidderivatives III (R¹⁷═Cl, Br, etc.) or carboxylic acid anhydrides III,particularly symmetric anhydrides, wherein R¹⁷ is a deprotonatedcarboxylic acid moiety such as e.g. pivaloylic acid, p-nitrobenzoicacid, p-trifluoromethylbenzoic acid, 2,4,6-trichloro benzoic acid,acetic acid, trifluoroacetic acid, carbonic acid monoisobutyl ester,diphenyl phosphinic acid or benzene sulfonic acid or the remainder of asecond moiety of formula (III) bound via an oxygen atom to form asymmetric anhydride is, are either commercially available, described inthe literature or can be prepared by methods well known to a personskilled in the art. Reacting compounds of formula III with compounds offormula II results in the formation of compounds of formula Ia or Ib(step a). Such amide bond formation reactions are well known in the art.E. g. if R¹⁷ is equal to chlorine or bromine such an amide bondformation can be performed in a solvent such as dichloromethane, in thepresence of a base such as triethylamine, ethyl-diisopropyl-amine orN-ethylmorpholine at temperatures between 0° C. and ambient temperature.Alternatively, compounds of formula Ia or Ib may be prepared bytreatment of anilines II with carboxylic acid anhydrides III in asolvent such as dichloromethane, in the presence of a base such astriethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine attemperatures between 0° C. and ambient temperature.

In addition, condensations of amines II with carboxylic acids III(R¹⁷═OH) can be performed using well known procedures for amideformation, such as the use ofN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride or BOP(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate)in the presence of a base such as ethyl-diisopropyl-amine,triethylamine, N-methylmorpholine optionally in the presence of4-dimethylamino-pyridine or HOBt (1-hydroxybenzo-triazole) in solventssuch as dichloromethane, DMF, DMA or dioxane at temperatures between 0°C. and ambient temperature.

If one of the starting materials II or III contains one or morefunctional groups which are not stable or are reactive under theconditions of the amide bond formation, appropriate protecting groups(as described e.g. in “Protective Groups in Organic Chemistry” by T. W.Greene and P. G. M. Wutts, 2^(nd) Ed., 1991, Wiley N.Y.) can beintroduced before the condensation step applying methods well known inthe art. Such protecting groups can be removed at a later stage of thesynthesis using standard methods described in the literature.

Compounds of the general formula Ia and Ib can contain one or morestereocenters and can optionally be separated into optically pureenantiomers or diastereomers by methods well known in the art, e. g. byHPLC chromatography, chromatography on a chiral HPLC column,chromatography with a chiral eluant or by derivatization of compound Ibwith an optically pure alcohol to form esters, which can be separated byconventional HPLC chromatography and then converted back to theenantiomerically pure acids Ib (R¹═H). In addition, racemic compounds Ibcan be separated into their antipodes via diastereomeric salts bycrystallization with optically pure amines such as e. g. (R) or(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,brucine, quinine or quinidine.

The preparation of compounds of formula Ib with R¹═H from compounds offormula Ia with R¹ not H is described in scheme 2 (step a). Thesehydrolysis reactions can be performed according to standard procedures,e. g. by treatment with an alkali hydroxide like LiOH or NaOH in a polarsolvent such as tetrahydrofuran, methanol, ethanol or water or mixturesthereof to give carboxylic acids Ib. In case R¹ is equal to tert-butyl,treatment with e. g. trifluoroacetic acid, optionally in the presence ofanisole in a solvent like dichloromethane or dichloroethane between roomtemperature and the reflux temperature of the solvents yields carboxylicacids Ib.

If the ester Ia contains one or more functional groups which are notstable under the hydrolysis conditions, appropriate protecting groups(as described e.g. in “Protective Groups in Organic Chemistry” by T. W.Greene and P. G. M. Wutts, 2^(nd) Ed., 1991, Wiley N.Y.) can beintroduced before the saponification, applying methods well known in theart. Subsequent hydrolysis and removal of the protecting group(s)provides carboxylic acid Ib.

Compounds of the general formula Ib can contain one or morestereocenters and can optionally be separated into optically pureenantiomers or diastereomers by methods well known in the art, e. g. byHPLC chromatography, chromatography on a chiral HPLC column,chromatography with a chiral eluant or by derivatization of compound Ibwith an optically pure alcohol to form esters, which can be separated byconventional HPLC chromatography and then converted back to theenantiomerically pure acids Ib. In addition, racemic compounds Ib can beseparated into their antipodes via diastereomeric salts bycrystallization with optically pure amines such as e. g. (R) or(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,brucine, quinine or quinidine.

An alternative synthesis for compounds Ic or Id with ((CR¹⁰R¹¹)_(m),with m=0) is depicted in scheme 3. Carboxylic acids IV (R¹⁷═OH) andcarboxylic acid derivatives IV (R¹⁷═Cl, Br) or carboxylic acidanhydrides IV are either commercially available, described in theliterature or can be prepared by methods well known to a person skilledin the art. Triflates IV (R¹⁸═OTf) can optionally be prepared from thecorresponding phenol derivates IV (R¹⁸═OH) by standard methods describedin the literature, e. g. using PhN(SO₂Tf)₂ in the presence of a baselike cesium carbonate in a solvent like N,N-dimethylformamide attemperatures around ambient temperature or in pyridine withtrifluoromethanesulfonic anhydride at 0° C. to ambient temperature.Condensations of anilines II with carboxylic acids IV (R¹⁷═OH) orcarboxylic acid derivatives IV (R¹⁷═Cl, Br) or carboxylic acidanhydrides IV to give amides V can be performed using standardprocedures described in the literature. E.g. if R¹⁷ is equal tochlorine, bromine or for the carboxylic acid anhydrides the reactioncould be performed in a solvent such as dichloromethane, in the presenceof a base such as triethylamine, ethyl-diisopropyl-amine orN-ethylmorpholine at temperatures between 0° C. and ambient temperature(step a). If R¹⁷ is equal to OH activating reagents like e. g.N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride or BOP(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate)in the presence of a base such as ethyl-diisopropyl-amine,triethylamine, N-methylmorpholine optionally in the presence of4-dimethylamino-pyridine or HOBt (1-hydroxybenzo-triazole) in solventssuch as dichloromethane, DMF, DMA or dioxane at temperatures between 0°C. and ambient temperature could be used.

Halides V (R¹⁸═Cl, Br, I), phenols V (R¹⁸═OH) or triflates V (R¹⁸═OTf)can be reacted with alcohols VI to give ethers Ic using methods wellknown in the art (step b). Phenols V (R¹⁸═OH) may be generated from theprotected phenols V (R¹⁸═OPG) prior to use by methods well known to theperson skilled in the art (as described e.g. in “Protective Groups inOrganic Chemistry” by T. W. Greene and P. G. M. Wutts, 2^(nd) Ed., 1991,Wiley N.Y.) and may be converted to the corresponding triflates V(R¹⁸═OTf) by standard methods described in the literature, e. g. usingPhN(SO₂Tf)₂ in the presence of a base like cesium carbonate in a solventlike N,N-dimethylformamide at temperatures around ambient temperature orin pyridine with trifluoromethanesulfonic anhydride at 0° C. to ambienttemperature. The alcohols VI are either commercially available,described in the literature or can be prepared by methods well known toa person skilled in the art. If halides V (R¹⁸═Cl, Br, I) are used asstarting material, compounds Ic can e. g. be prepared in the presence ofCuI, cesium carbonate and 8-hydroxychinoline in a solvent like1-methyl-2-pyrrolidone (see for example Z. J. Song et al., OrganicLetters, 4, 1623; 2002). Starting from triflates V (R¹⁸═OTf), ethers Icor Id can be synthesized applying e. g. the procedure from Larock et al.(R. C. Larock et al., Organic Letters, 6, 99; 2004) using CsF inacetonitrile at ambient temperature. In addition, several transitionmetal mediated procedures for the formation of aryl ethers are reportedin the literature (see e. g. J. F. Hartwig et al., J. Am. Chem. Soc.,121, 3224; 1999).

Alternatively, phenols V (R¹⁸═OH) may be treated with alcohols VI usingMitsunobu (e.g. O. Mitsunobu, Synthesis 1981,1.) conditions to yieldcompounds Ic. This transformation is preferably carried out withtriphenylphosphine and di-tert-butyl-, diisopropyl- ordiethyl-azodicarboxylate as reagents, in a solvent like toluene,dichloromethane or tetrahydrofuran at 0° C. to ambient temperature.

Alternatively, compounds Ic and Id may be prepared from phenol V(R¹⁸═OH) by alkylation with compounds VII (R¹⁹═Br, Cl, I, MsO, TsO, TfO)in solvents such as acetone, acetonitrile, DMF, DMA or THF in thepresence of bases such as K₂CO₃, Cs₂CO₃ or ethyl-diisopropyl-amine atambient temperature to reflux (step c).

Aryl ethers Ic with an ester group (R¹≠H) can be hydrolyzed according tostandard procedures, e. g. by treatment with an alkali hydroxide likeLiOH or NaOH in a polar solvent mixture liketetrahydrofurane/ethanol/water to give carboxylic acids of formula Id(R¹═H) (step d). In case R¹ is equal to tert-butyl, treatment with e. g.trifluoroacetic acid, optionally in the presence of anisole in a solventlike dichloromethane or dichloroethane between room temperature and thereflux temperature of the solvents yields carboxylic acids Id (step d).

If one of the starting materials II, IV, V, VI, or VII contains one ormore functional groups which are not stable or are reactive under theconditions of the amide bond formation, appropriate protecting groups(as described e.g. in “Protective Groups in Organic Chemistry” by T. W.Greene and P. G. M. Wutts, 2^(nd) Ed., 1991, Wiley N.Y.) can beintroduced before the condensation step, applying methods well known inthe art. Such protecting groups can be removed at a later stage of thesynthesis using standard methods described in the literature.

Compounds of the general formula Ic and Id can contain one or morestereocenters and can optionally be separated into optically pureenantiomers or diastereomers by methods well known in the art, e. g. byHPLC chromatography, chromatography on a chiral HPLC column,chromatography with a chiral eluant or by derivatization of compounds Idwith an optically pure alcohol to form esters, which can be separated byconventional HPLC chromatography and then converted back to theenantiomerically pure acids Id. In addition, racemic compounds Id can beseparated into their antipodes via diastereomeric salts bycrystallization with optically pure amines such as e. g. (R) or(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,brucine, quinine or quinidine.

An alternative synthesis for compounds Ic or Id (m=1) is depicted inscheme 4. Carboxylic acids IV (R²⁰═OH, OPG) and carboxylic acidderivatives IV (R¹⁷═Cl, Br) or carboxylic acid anhydrides IV are eithercommercially available, described in the literature or can be preparedby methods well known to a person skilled in the art. Condensations ofanilines II with carboxylic acids IV (R¹⁷═OH) or carboxylic acidderivatives IV (R¹⁷═Cl, Br) or carboxylic acid anhydrides IV to giveamides V can be performed using standard procedures described in theliterature. E.g. if R¹⁷ is equal to chlorine or bromine or for thecarboxylic acid anhydrides the reaction could be performed in a solventsuch as dichloromethane, in the presence of a base such astriethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine attemperatures between 0° C. and ambient temperature (step a). If R¹⁷ isequal to OH activating reagents like e. g.N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride or BOP(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate)in the presence of a base such as ethyl-diisopropyl-amine,triethylamine, N-methylmorpholine optionally in the presence of4-dimethylamino-pyridine or HOBt (1-hydroxybenzo-triazole) in solventssuch as dichloromethane, DMF, DMA or dioxane at temperatures between 0°C. and ambient temperature could be used.

Alcohols V (R²⁰═OH) can be reacted with alcohols VI to give ethers Icusing methods well known in the art (step b). Alcohols V may begenerated from the protected alcohols V (R²⁰═OPG) prior to use bymethods well known to the person skilled in the art (as described e.g.in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M.Wutts, 2^(nd) Ed., 1991, Wiley N.Y.). The alcohols VI are eithercommercially available, described in the literature or can be preparedby methods well known to a person skilled in the art. For the reactionof alcohols V with alcohols VI (n=0) Mitsunobu conditions may be used togive compounds Ic. This transformation is preferably carried out withtriphenylphosphine and di-tert-butyl-, diisopropyl- ordiethyl-azodicarboxylate as reagents, in a solvent like toluene,dichloromethane or tetrahydrofuran at 0° C. to ambient temperature.

Alternatively, alcohol V may be converted to the corresponding mesylateor tosylate V (R²⁰═OMs, OTs) by treatment with methanesulfonyl chlorideor para-toluenesulfonyl chloride, respectively, in CH₂Cl₂ in thepresence of a base such as pyridine or ethyl-diisopropyl-amineoptionally in the presence of DMAP at temperatures between 0° C. toambient temperature (step c). The corresponding triflates V (R²⁰═OTf)may be prepared in pyridine with trifluoromethanesulfonic anhydride at0° C. to ambient temperature. Reaction of compounds V (R²⁰═OMs, OTs,OTf) with alcohols VI in the presence of sodium hydride in solvents suchas DMF or THF at temperatures between 0° C. to reflux of the solventgives compounds Ic (step d).

Alternatively, compounds Ic and Id may be prepared from alcohol V(R²⁰═OH) by alkylation with compounds VII (R²¹═Br, Cl, I, MsO, TsO, TfO)in the presence of sodium hydride in solvents such as DMF or THF attemperatures between 0° C. to reflux of the solvent (step e).

Aryl ethers Ic with an ester group (R¹≠H) can be hydrolyzed according tostandard procedures, e. g. by treatment with an alkali hydroxide likeLiOH or NaOH in a polar solvent mixture liketetrahydrofurane/ethanol/water to give carboxylic acids of formula Id(R¹═H) (step f). In case R¹ is equal to tert-butyl, treatment with e. g.trifluoroacetic acid, optionally in the presence of anisole in a solventlike dichloromethane or dichloroethane between room temperature and thereflux temperature of the solvents yields carboxylic acids Id (step d).

If one of the starting materials II, IV, V, VI, or VII contains one ormore functional groups which are not stable or are reactive under theconditions of the amide bond formation, appropriate protecting groups(as described e.g. in “Protective Groups in Organic Chemistry” by T. W.Greene and P. G. M. Wutts, 2^(nd) Ed., 1991, Wiley N.Y.) can beintroduced before the condensation step applying methods well known inthe art. Such protecting groups can be removed at a later stage of thesynthesis using standard methods described in the literature.

Compounds of the general formula Ic and Id can contain one or morestereocenters and can optionally be separated into optically pureenantiomers or diastereomers by methods well known in the art, e. g. byHPLC chromatography, chromatography on a chiral HPLC column,chromatography with a chiral eluant or by derivatization of acids Idwith an optically pure alcohol to form esters, which can be separated byconventional HPLC chromatography and then converted back to theenantiomerically pure acids Id. In addition, racemic compounds Id can beseparated into their antipodes via diastereomeric salts bycrystallization with optically pure amines such as e. g. (R) or(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,brucine, quinine or quinidine.

Compounds of the general formula Ic/Id can contain one or morestereocenters and can optionally be separated into optically pureenantiomers or diastereomers by methods well known in the art, e. g. byHPLC chromatography, chromatography on a chiral HPLC column,chromatography with a chiral eluant or by derivatization with anoptically pure alcohol to form esters, which can be separated byconventional HPLC chromatography and then converted back to theenantiomerically pure acids Id. In addition, racemic compounds can beseparated into their antipodes via diastereomeric salts bycrystallization with optically pure amines such as e. g. (R) or(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,brucine, quinine or quinidine.

The conversion of a compound of formula (I) into a pharmaceuticallyacceptable salt can be carried out by treatment of such a compound withphysiologically compatible bases. Examples of such salts are alkaline,earth-alkaline and ammonium salts such as e.g. Na—, K—, Ca— andtrimethylammonium-salt. One method to form such a salt is e.g. byaddition of 1/n equivalents of a basic salt such as e.g. M(OH)_(n),wherein M=metal or ammonium cation and n=number of hydroxide anions, toa solution of the compound in a suitable solvent (e.g. ethanol,ethanol-water mixture, tetrahydrofurane-water mixture) and to remove thesolvent by evaporation or lyophilisation

The conversion of compounds of formula (I) into pharmaceuticallyacceptable esters can be carried out e.g. by treatment of a suitablecarboxy group present in the molecule with a suitable alcohol using e.g.a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), N,N-dicylohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) orO-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluorborate(TPTU). Pharmaceutically acceptable esters can furthermore be preparedby treatment of a suitable hydroxy group present in the molecule with asuitable acid, optionally or if necessary in the presence of acondensating agent as described above.

Insofar as their preparation is not described in the examples, thecompounds of formula (I) as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth above. Starting materials are commercially available or known inthe art.

As described above, the compounds of formula (I) of the presentinvention and compounds selected from the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy) methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,    can be used as medicaments for the treatment and/or prevention of    diseases which are modulated by HM74A agonists. Examples of such    diseases are increased lipid and cholesterol levels, particularly    dyslipidemia, low HDL-cholesterol, atherosclerotic diseases,    hypertriglyceridemia, thrombosis, angina pectoris, peripheral    vascular disease, stroke, diabetes, particularly non-insulin    dependent diabetes mellitus, metabolic syndrome, Alzheimer's    disease, Parkinson's disease, schizophrenia, sepsis, inflammatory    diseases (such as e.g. colitis, pancreatitis, cholestasis/fibrosis    of the liver, and diseases that have an inflammatory component such    as e.g. Alzheimer's disease or impaired/improvable cognitive    function). The use as medicament for the treatment of    atherosclerosis, low HDL cholesterol levels, non-insulin dependent    diabetes mellitus, and the metabolic syndrome is preferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as described above or a compound selected from thegroup consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoic]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,-   and a pharmaceutically acceptable carrier and/or adjuvant.

Further the invention relates to compounds as described above orcompounds selected from the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoic]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,    for use as therapeutic active substances, especially as therapeutic    active substances for the treatment and/or prevention of diseases    which are modulated by HM74A agonists, particularly as    therapeutically active substances for the treatment and/or    prevention of increased lipid levels, increased cholesterol levels,    atherosclerotic diseases, dyslipidemia, low HDL-cholesterol,    hypertriglyceridemia, thrombosis, angina pectoris, peripheral    vascular disease, stroke, diabetes, non-insulin dependent diabetes    mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's    disease, schizophrenia, impaired or improvable cognitive function,    sepsis, inflammatory diseases, colitis, pancreatitis and    cholestasisfibrosis of the liver.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are modulated by HM74Aagonists, particularly for the treatment and/or prevention of increasedlipid levels, increased cholesterol levels, atherosclerotic diseases,dyslipidemia, low HDL-cholesterol, hypertriglyceridemia, thrombosis,angina pectoris, peripheral vascular disease, stroke, diabetes,non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer'sdisease, Parkinson's disease, schizophrenia, impaired or improvablecognitive function, sepsis, inflammatory diseases, colitis, pancreatitisand cholestasisfibrosis of the liver, which method comprisesadministering a compound as described above or a compound selected fromthe group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy) methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,-   to a human or animal.

The invention further relates to the use of compounds as defined aboveor compounds selected from the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy) methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,    for the treatment and/or prevention of diseases which are modulated    by HM74A agonists, particularly for the treatment and/or prevention    of increased lipid levels, increased cholesterol levels,    atherosclerotic diseases, dyslipidemia, low HDL-cholesterol,    hypertriglyceridemia, thrombosis, angina pectoris, peripheral    vascular disease, stroke, diabetes, non-insulin dependent diabetes    mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's    disease, schizophrenia, impaired or improvable cognitive function,    sepsis, inflammatory diseases, colitis, pancreatitis and    cholestasisfibrosis of the liver.

In addition, the invention relates to the use of compounds as describedabove or compounds selected from the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and

2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid 1-methylethylester,

for the preparation of medicaments for the treatment and/or preventionof diseases which are modulated by HM74A agonists, particularly for thetreatment and/or prevention of increased lipid levels, increasedcholesterol levels, atherosclerotic diseases, dyslipidemia, lowHDL-cholesterol, hypertriglyceridemia, thrombosis, angina pectoris,peripheral vascular disease, stroke, diabetes, non-insulin dependentdiabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson'sdisease, schizophrenia, impaired or improvable cognitive function,sepsis, inflammatory diseases, colitis, pancreatitis andcholestasisfibrosis of the liver. Such medicaments comprise a compoundas described above.

Prevention and/or treatment of atherosclerosis, low HDL cholesterollevels, non-insulin dependent diabetes mellitus, and the metabolicsyndrome is preferred.

In the above mentioned compositions, uses and methods, compounds offormula (I) as described above are preferred over the compounds selectedfrom the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl) methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxyl benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy) methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester.

In the compositions, methods and uses described above, of the compoundsselected from the group consisting of:

-   5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic    acid,-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[(4-phenoxybenzoyl)amino]-benzoic acid,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,-   the compounds selected from the group consisting of:-   2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,-   2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2,4-dichlorophenoxy) methyl]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic    acid methyl ester,-   2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid    methyl ester,-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl    ester,-   2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl    ester, and-   2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid    1-methylethyl ester,-   are preferred.

The following tests were carried out in order to determine thebiological activity of the compounds of formula (I).

Primary Radiolabelled Ligand Competition Binding Assay

Nicotinic acid binding assays were performed with membrane preparations.A cell pellet containing 1×10⁸ HEK-293 cells, stably transfected withthe HM74A receptor, was resuspended in 3 ml of ice cold Dounce Buffer(10 mM Tris-Cl p.H 7.6, 0.5 mM MgCl₂) supplemented with Roche proteaseinhibitor cocktail and homogenized at high speed on a Polytronhomogenizer two times for 20 sec on ice. Nuclei and unbroken cells wereremoved by centrifugation for 5 min at 1,000×g after the addition of 1ml of tonicity restoration buffer (10 mM Tris pH 7.6, 0.5 mM MgCl₂, 600mM NaCl). The homogenate was centrifuged at 60,000×g for 30 min andpellets were resuspended in Tris buffer (50 mM Tris pH 7.4, containingprotease inhibitors). Binding reactions contained 20 μg membranes asdetermined by BCA protein assay (Pierce), 50 nM [³H]-nicotinic acid(Amersham) with or without compound addition in 250 μl of binding buffer(50 mM Tris pH 7.4, 2 mM MgCl₂, 0.02 % CHAPS). Incubations were carriedout at room temperature for 2 hrs and terminated by filtration using aFiltermate Harvester (PerkinElmer) onto GF/C filter plates (Millipore).Bound [³H]-nicotinic acid was determined by scintillation counting usingTop Count NXT (PerkinElmer). Compounds were dissolved in a concentrationof 10⁻² or 10⁻³ M in DMSO, further dilutions were performed in bindingbuffer. The effects of compounds were expressed as % inhibition of[³H]-nicotinic acid binding.Sigmoidal curves were fitted using theXLfit3 program (ID Business Solutions Ltd. UK) and IC₅₀ valuesdetermined.

The compounds of the present invention exhibit IC₅₀ values in a range ofabout 0.001 μM to about 100 μM in the binding assay. Preferably, thecompounds of the present invention have IC₅₀ values in a range of about0.001 μM to about 10.0 μM, more preferably about 0.001 μM to about 1 μM.

Secondary Fluorescent Calcium Indicator Assay (FLIPR)

HEK-293 cells were grown in tissue culture medium (DMEM/Nut mix F12Medium with Glutamax I (Invitrogen), containing 10% FBS) at 37° C. in a5% CO₂ atmosphere. These cells were cultured in 6-well dishes at 3×10⁵cells/well and double transfected with DNA vectors (pcDNA3.1,Invitrogen) expressing either HM74A or HM74 and the chimeric G proteinGqi9. Two days after transfection the wells were combined and plated in150 cm² flasks, in the presence of 50 μg/ml Hygromycin (Invitrogen) and500 μg/ml Geneticin (Gibco). Fourteen days after plating, colonies werepicked, expanded and analyzed for expression using a functional assay(FLIPR). Stable transfected HEK-293 cells expressing either HM74A orHM74 and the chimeric G protein Gqi9 were plated at 50,000 cells/well inblack 96-well plates with clear bottom (Costar) and cultured toconfluency overnight in growth media (DMEM/Nut mix F12 Medium withGlutamax I (Invitrogen), containing 10% FBS) at 37° C. in a humidifiedcell incubator containing 5% CO₂. Growth media was aspirated andreplaced with 100 μl of 1× FLIPR Calcium Assay Dye (Molecular Devices)in Hank's balanced salt solution (HBSS) containing 10 mM HEPES, and 250mM probenecid (Sigma), for 1 hour at 37° C. Cell plates were transferredto a FLIPR unit (Molecular Devices), and 50 μl of 3× compound dilutionwere added. Fluorescence emissions were measured and the effects ofcompounds were expressed as % stimulation of maximal nicotinic acidresponse (100 μM). Sigmoidal curves were fitted using the XLfit3 program(ID Business Solutions Ltd. UK) and EC₅₀ values determined.

The compounds of the present invention exhibit EC₅₀ values in a range ofabout 0.001 μM about 100 μM in the FLIPR assay. Preferably, thecompounds of the present invention have EC₅₀ values in a range of about0.001 μM to about 10.0 μM; more preferably about 0.001 μM to about 1 μM.

In the following table, EC50 values for some of the compounds of thepresent invention are shown. Example EC₅₀ HM74A [μM] 2 1.100 17 0.529 290.101

The compounds of formula I and/or their pharmaceutically acceptablesalts can be used as medicaments, e.g. in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatine capsules, solutions,emulsions or suspensions, rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions or suspensions orinfusion solutions, or topically, e.g. in the form of ointments, creamsor oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 5000 mg,preferably about 1 to 1000 mg, especially about 1 to 300 mg, comes intoconsideration. Depending on severity of the disease and the precisepharmacokinetic profile the compound could be administered with one orseveral daily dosage units, e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-1000 mg,preferably 1-300 mg, more preferably 1-100 mg, of a compound of formulaI.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

General Remarks

The reactions were performed under argon where appropriate.

Example 1 2-(4-Benzyloxy-benzoylamino)-benzoic acid

Step 1:

2-(4-Benzyloxy-benzoylamino)-benzoic acid methyl ester

To 2-amino-benzoic acid methyl ester (0.51 mL) and triethylamine (0.69mL) in dichloromethane (31 mL) at −50° C. was slowly added a solution of4-benzyloxy-benzoyl chloride [1486-50-6](1 g) in 31 mL ofdichloromethane. The reaction mixture was then allowed to warm up toroom temperature and stirred for an additional hour. After such time,the reaction mixture was washed with water. The aqueous phase wasfurther extracted with dichloromethane. The combined organic phases weredried over sodium sulfate and concentrated in vacuo. The residue waspurified by column chromatography (heptane-ethyl acetate: 0-50%) toyield 2-(4-benzyloxy-benzoylamino)-benzoic acid methyl ester (400 mg).MS (m/e): 362.5 (M+H⁺, 100%).

Step 2:

2-(4-Benzyloxy-benzoylamino)-benzoic acid

To 2-(4-benzyloxy-benzoylamino)-benzoic acid methyl ester (50 mg) inmethanol (3 mL) was added lithium hydroxide monohydrate (6.3 mg) and thereaction mixture was stirred at room temperature until the reaction wascomplete. The reaction mixture was then reacidified using 1 N HCl andthe product was then purified by column chromatography (SiO₂, ethylacetate-ethanol: 0-20%) to give 2-(4-benzyloxy-benzoylamino)-benzoicacid as a white solid (39 mg). MS (m/e): 346.3 (M−H⁻, 100%).

Example 2 2-[4-(4-Fluoro-phenoxy)-benzoylamino]-benzoic acid

To 2-(4-iodo-benzoylamino)-benzoic (acid methyl ester [75541-84-3](50mg) in 1-methyl-2-pyrrolidinone (1 mL) was added 4-fluorophenol (29.4mg), copper (I) chloride (6.6 mg), cesium carbonate (85 mg) and8-hydroxy-chinolin (4.7 mg). The reaction mixture was stirred at 120° C.for 18 hours. After such time, the reaction mixture was allowed to cooldown to room temperature, diluted with water, formic acid was added (0.3mL) and the solution was purified by preparative HPLC to yield2-[4-(4-fluoro-phenoxy)-benzoylamino]-benzoic acid (49.1 mg). MS (m/e):332.1 (M−H⁻, 100%).

Example 3 2-[4-(3,4-Dichloro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(3,4-Dichloro-phenoxy)-benzoylamino]-benzoic acid was prepared from2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and3,4-dichlorophenol. MS (m/e): 400.0 (M−H⁻, 100%).

Example 4 2-(4-p-Tolyloxy-benzoylamino)-benzoic acid

In analogy to example 2, 2-(4-p-Tolyloxy-benzoylamino)-benzoic acid wasprepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and p-cresol. MS (m/e): 346.3 (M−H⁻, 100%).

Example 5 2-[4-(3-Methoxy-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(3-Methoxy-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 3-methoxy-phenol. MS (m/e): 362.4 (M−H⁻, 100%).

Example 6 2-(4-o-Tolyloxy-benzoylamino)-benzoic acid

In analogy to example 2, 2-(4-o-Tolyloxy-benzoylamino)-benzoic acid wasprepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and o-cresol. MS (m/e): 346.1 (M−H⁻, 100%).

Example 7 2-[4-(4-Methoxy-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(4-Methoxy-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 4-methoxy-phenol. MS (m/e): 362.4 (M−H⁻, 100%).

Example 8 2-[4-(4-Chloro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(4-Chloro-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 4-chloro-phenol. MS (m/e): 366.1 (M−H⁻, 100%).

Example 9 2-[4-(3,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(3,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid was prepared from2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and3,4-difluoro-phenol. MS (m/e): 368.3 (M−H⁻, 100%).

Example 10 2-[4-(4-Methanesulfonyl-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(4-Methanesulfonyl-phenoxy)-benzoylamino]-benzoic acid was preparedfrom 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and4-(methylsulfonyl)-phenol. MS (m/e): 368.3 (M−H⁻, 100%).

Example 11 2-{4-[4-Methoxycarbonyl)phenoxy]benzoyl}aminobenzoic acid

In analogy to example 2,2-{4-[4-Methoxycarbonyl)phenoxy]benzoyl}aminobenzoic acid was preparedfrom 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and4-hydroxy-benzoic acid methyl ester. MS (m/e): 390.3 (M−H⁻, 100%).

Example 12 2-[4-(3,5-Dichloro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(3,5-Dichloro-phenoxy)-benzoylamino]-benzoic acid was prepared from2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and from3,5-dichloro-phenol. MS (m/e): 400.1 (M−H⁻, 100%).

Example 13 2-[4-(4-Cyano-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(4-Cyano-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 4-hydroxybenzonitrile. MS (m/e): 357.1 (M−H⁻, 100%).

Example 14 2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 2-fluorophenol. MS (m/e): 350.4 (M−H⁻, 100%).

Example 15 2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 2-chloro-phenol. MS (m/e): 365.9 (M−H⁻, 100%).

Example 16 2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 3-fluoro-phenol. MS (m/e): 350.0 (M−H⁻, 100%).

Example 17 2-[4-(3-Chloro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(3-Chloro-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 3-chloro-phenol. MS (m/e): 366.0 (M−H⁻, 100%).

Example 18 2-(4-m-Tolyloxy-benzoylamino)-benzoic acid

In analogy to example 2, 2-(4-m-Tolyloxy-benzoylamino)-benzoic acid wasprepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and m-cresol. MS (m/e): 346.3 (M−H⁻, 100%).

Example 19 2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and quinolin-8-ol. MS (m/e): 383.0 (M−H⁻, 100%).

Example 20 2-[4-(4-Trifluoromethyl-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(4-Trifluoromethyl-phenoxy)-benzoylamino]-benzoic acid was preparedfrom 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and4-trifluororomethyl phenol. MS (m/e): 399.8 (M−H⁻, 100%).

Example 21 2-[4-(4-Carbamoyl-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(4-Carbamoyl-phenoxy)-benzoylamino]-benzoic acid was prepared from2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and4-hydroxy-benzamide. MS (m/e): 375.0 (M−H⁻, 100%).

Example 22 2-[4-(4-Dimethylaminomethyl-phenoxy)-benzoylamino]-benzoicacid

In analogy to example 2,2-[4-(4-Dimethylaminomethyl-phenoxy)-benzoylamino]-benzoic acid wasprepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3] and 4-dimethylaminomethyl-phenol. MS (m/e): 389.0 (M−H⁻,100%).

Example 23 2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoicacid

In analogy to example 2,2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoic acid wasprepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 4-[1,2,4]triazol-1-yl-phenol. MS (m/e): 398.9 (M−H⁻,100%).

Example 24 2-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 2,4-difluoro-phenol. MS (m/e): 367.1 (M−H⁻, 100%).

Example 25 2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 2-hydroxypyridine. MS (m/e): 333.4 (M−H⁻, 100%).

Example 26 2-[4-(Pyridin-3-yloxy)-benzoylamino]-benzoic acid

In analogy to example 2, 2-[4-(Pyridin-3-yloxy)-benzoylamino]-benzoicacid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester[75541-84-3]and 3-hydroxypyridine. MS (m/e): 333.3 (M−H⁻, 100%).

Example 27 2-[4-(3,4-Dimethyl-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(3,4-Dimethyl-phenoxy)-benzoylamino]-benzoic acid was prepared from2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and3,4-dimethylphenol. MS (m/e): 362.4 (M−H⁻, 100%).

Example 28 2-[4-(2,3-Difluoro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(2,3-Difluoro-phenoxy)-benzoylamino]-benzoic acid was prepared from2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and2,3-difluorophenol. MS (m/e): 368.1 (M−H⁻, 100%).

Example 29 2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid was prepared from2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3]and2,5-difluorophenol. MS (m/e): 368.1 (M−H⁻, 100%).

Example 30 2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid

Step 1:

2-(4-Bromo-3-methyl-benzoylamino)-benzoic acid methyl ester

To 2-amino-benzoic acid methyl ester (3.1 g) in dichloromethane (31 mL)was slowly added 4-bromo-3-methyl-benzoyl chloride [21900-25-4](4.8 g)and triethylamine (3.1 mL). The reaction mixture was then stirred atroom temperature for 1 hour. After such time, the reaction mixture wasfurther diluted with dichloromethane (50 mL) and washed with water. Thecombined aqueous phase was further extracted with dichloromethane. Allcombined organic phases were then dried over sodium sulfate andconcentrated in vacuo. The residue was then recrystallised from ethanolto give 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester(6.14 g) as white crystals, m.p.=123° C. MS (m/e): 348.3 (M+H⁺, 100%).

Step 2:

2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid

In analogy to example 2, 2-(3-Methyl-4-phenoxy-benzoylamino)-benzoicacid was prepared from 2-(4-bromo-3-methyl-benzoylamino)-benzoic acidmethyl ester and phenol. MS (m/e): 346.3 (M−H⁻, 100%).

Example 31 2-(2-Methyl-4-phenoxy-benzoylamino)-benzoic acid

In analogy to example 30, 2-(2-Methyl-4-phenoxy-benzoylamino)-benzoicacid was prepared using 4-bromo-2-methyl-benzoyl chloride [21900-45-8]instep 1 and phenol in step 2. MS (m/e): 346.3 (M−H⁻, 100%).

Example 32 2-(2-Methoxy-4-phenoxy-benzoylamino)-benzoic acid

In analogy to example 30, 2-(2-Methoxy-4-phenoxy-benzoylamino)-benzoicacid was prepared using 4-bromo-2-methoxy-benzoyl chloride [5213-16-1]instep 1 and phenol in step 2. MS (m/e): 346.3 (M−H⁻, 100%).

Example 33 5-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid

In analogy to example 1, 5-Fluoro-2-(4-phenoxy-benzoylamino)-benzoicacid was prepared form 2-amino-5-fluoro-benzoic acid and4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.4 (M−H⁻, 100%).

Example 34 4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid

In analogy to example 1, 4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoicacid was prepared from 2-amino-4-fluoro-benzoic acid and4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.0 (M−H⁻, 100%).

Example 35 2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid

In analogy to example 1, 2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoicacid was prepared from 2-amino-6-fluoro-benzoic acid and4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.1 (M−H⁻, 100%).

Example 36 2-[4-(3-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid

Step 1:

2-(4-Bromo-3-methyl-benzoylamino)-benzoic acid methyl ester

To 2-amino-benzoic acid methyl ester (3.1 g) in dichloromethane (31 mL)under slight cooling was added 3-methyl-4-bromobenzoyl chloride([21900-25-4], 4.8 g) followed by a triethylamine (3.15 mL). Thetemperature of the solution was kept below 40° C. and the reactionmixture was then stirred at room temperature for an hour. After suchtime, additional dichloromethane was added (50 mL) and the reactionmixture was washed with water. The aqueous phase was further extractedwith dichloromethane. The combined organic phases were dried over sodiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography (heptane-ethyl acetate: 0-50%) to yield2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester (7.1 g). MS(m/e): 348.3 (M+H⁺, 100%).

Step 2:

2-[4-(3-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid

In analogy to example 2,2-[4-(3-fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid was preparedfrom 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester and3-fluorophenol. MS (m/e): 364.0 (M−H⁻, 100%).

Example 37 2-[4-(2-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid

In analogy to example 36,2-[4-(2-fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid was preparedfrom 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester and2-fluorophenol. MS (m/e): 364.0 (M−H⁻, 100%).

Example 38 2-[4-(2,4-Difluoro-phenoxy)-3-methyl-benzoylamino]-benzoicacid

In analogy to example 36,2-[4-(2,4-difluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid wasprepared from 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methylester and 2,4-difluorophenol. MS (m/e): 382.0 (M−H⁻, 100%).

Example 39 4-Chloro-5-fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid

Step 1:

N,N-di-tert-Butyloxycarbonyl-2-bromo-5-chloro-4-fluoro-aniline

This compound was prepared in analogy to the method of Darnbrough et al.(Synth. Comm. 2001, 31, 3273): Under an atmosphere of Nitrogen,di-tert-butyl dicarbonate [24424-99-5], 8.839 g) was added to a cooled(0° C.) solution of 2-bromo-5-chloro-4-fluoro-aniline ([85462-59-5],3.03 g) and DMAP (0.165 g) in THF (20 ml). After 4 h at r.t., thereaction mixture was taken up in ethyl acetate, washed with 1N HCl andbrine, and dried (Na₂SO₄). The solvent was evaporated and the residuepurified by column chromatography (silica gel, n-heptane, ethyl acetate)to give the title compound (4.66 g, 81%). ¹H NMR (CDCl₃): δ 1.42 (s,18H), 7.28 (d, 1H), 7.42 (d, 1H).

Step 2:

2-tert-Butyloxycarbonylamino-4-chloro-5-fluoro-benzoic acid tert-butylester

This compound was prepared in analogy to the method of Herzig et al.(Synlett 2005, 3107): Under an atmosphere of Nitrogen, a solution ofn-butyl lithium in hexane (1.6N, 3.72 ml) was added dropwise at atemperature of −78° C. to a solution ofN,N-di-tert-butyloxycarbonyl-2-bromo-5-chloro-4-fluoro-aniline (2.3 g)in THF (10 ml). After 30 min, the mixture was allowed to warm to r.t.,then quenched with satd. NH₄Cl, and extracted with ethyl acetate. Theextract was dried (Na₂SO₄) and evaporated. The residue was purified bycolumn chromatography (silica gel, n-heptane, ethyl acetate) to give thetitle compound (0.68 g, 36%). ¹H NMR (CDC₃): δ 1.42 (s, 9H), 1.60 (s,9H), 7.70 (d, 1H), 8.62 (d, 1H), 10.25 (bs, 1H).

Step 3:

4-Chloro-5-fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid

Under an atmosphere of Argon,2-tert-butoxycarbonylamino-4-chloro-5-fluoro-benzoic acid tert-butylester (200 mg) and 4-phenoxy-benzoyl chloride ([1623-95-6], 269 mg) weredissolved in THF (5 mL). Triethylamine (0.24 ml) was added, and themixture was heated to reflux overnight. The solvent was evaporated, andthe residue was purified by column chromatography (silicagel/methanol/dichloromethane). The eluate, which contained twoUV-absorbing components, was evaporated, and the residue was dissolvedin a mixture of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5ml). After 2 h, the volatiles were evaporated, and the title compound (9mg, 0.4%) was isolated from the mixture by preparative, reversed-phaseHPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH₃CN in0.1% TFA(aq) over 4.5 min, flow rate 30 ml/min). MS: m/e=384.1 [M+H⁺].

Example 40 2-(4-Phenoxy-benzoylamino)-5-trifluoromethyl-benzoic acid

In analogy to example 39,2-(4-phenoxy-benzoylamino)-5-trifluoromethyl-benzoic acid was preparedfrom 2-bromo-4-trifluoromethyl-phenylamine (57946-63-1). ¹H NMR(d⁶-DMSO): δ 7.14-7.18 (4H, m), 7.25-7.28 (1H, m), 7.45-7.50 (2H, m),8.00-8.02 (2H, m), 8.04-8.05 (1H, m), 8.28-8.29 (1H, m), 8.90-8.92 (1H,m), 12.33 (1H, bs), 14.40 (1H, bs).

Example 41

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner: Ingredients Per tablet Kernel:Compound of formula (I) 10.0 mg 200.0 mg  Microcrystalline cellulose23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate  1.5mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg  Film Coat: Hydroxypropylmethyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mgTalc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidon in water. The granulate is mixed with sodium starchglycolate and magesiumstearate and compressed to yield kernels of 120 or350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example 42

Capsules containing the following ingredients can be manufactured in aconventional manner: Ingredients Per capsule Compound of formula (I)25.0 mg Lactose 150.0 mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example 43

Injection solutions can have the following composition: Compound offormula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg Acetic Acid q.s. adpH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by AceticAcid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

Example 44

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner: Capsule contents Compound offormula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mgPartially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weightof capsule contents 165.0 mg Gelatin capsule mg Gelatin 75.0 Glycerol85% 32.0 mg Karion 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Ironoxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example 45

Sachets containing the following ingredients can be manufactured in aconventional manner: Compound of formula (I) 50.0 mg Lactose, finepowder 1015.0 mg  Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg Sodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcristalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavoring additives and filled into sachets.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of formula (I):

wherein R¹ is hydrogen or lower-alkyl; R², R³, R⁴ and R⁵, independentlyfrom each other, are hydrogen, halogen, lower-alkyl orfluoro-lower-alkyl, with the proviso that R⁴is not bromine; R⁶, R⁷, R⁸and R⁹, independently from each other, are hydrogen, lower-alkyl,lower-alkoxy, cycloalkyl, halogen, lower-alkoxy-lower-alkyl,fluoro-lower-alkyl, fluoro-lower-alkoxy, lower alkenyl, lower alkinyl orcyano; R¹⁰, R¹¹, R¹² and R¹³ independently from each other are hydrogen,lower-alkyl or fluoro-lower-alkyl, or R¹⁰ and R¹¹ are bound together toform a cycloalkyl together with the carbon atom to which they areattached and —R¹⁰—R¹¹— is —(CH₂)₂₋₆—, or R¹² and R¹³ are bound togetherto form a cycloalkyl together with the carbon atom to which they areattached and —R¹²—R¹³— is —(CH₂)₂₋₆—; R¹⁴ is phenyl or heteroaryl, whichphenyl or heteroaryl is optionally substituted with 1 to 3 substituentsselected from the group consisting of halogen, lower-alkyl,hydroxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, carboxy,carboxy-lower-alkyl, lower-alkoxy-carbonyl,lower-alkoxy-carbonyl-lower-alkyl, R¹⁵R¹⁶NC(O), R¹⁵R¹⁶NC(O)-lower-alkyl,fluoro-lower-alkyl, R¹⁵R¹⁶N-lower-alkyl, R¹⁵R¹⁶N, lower-alkyl-SO₂,lower-alkyl-SO₂O, lower-alkyl-SO₂-NR¹⁵, R¹⁵R¹⁶NSO₂, cyano, heteroaryl,cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl,fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl; R¹⁵ and R¹⁶independently from each other are hydrogen or lower-alkyl; m is 0 or 1;n is 0 or 1; and pharmaceutically acceptable salts and pharmaceuticallyacceptable esters thereof; with the proviso that the compound of formula(I) is not selected from the group consisting of:5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoicacid, 2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[(4-phenoxybenzoyl)amino]-benzoic acid,2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester,2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic acidmethyl ester,2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester, and 2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoicacid 1-methylethyl ester.
 2. The compound according to claim 1, whereinR¹ is hydrogen.
 3. The compound according to claim 1, wherein R², R³, R⁴and R⁵, independently from each other, are hydrogen or halogen, with theproviso that R⁴ is not bromine.
 4. The compound according to claim 1,wherein R² is hydrogen or fluorine.
 5. The compound according to claim1, wherein R³ is hydrogen.
 6. The compound according to claim 1, whereinR⁴ is hydrogen or fluorine.
 7. The compound according to claim 1,wherein R⁵ is hydrogen.
 8. The compound according to claim 1, whereinR⁶, R⁷, R⁸ and R⁹, independently from each other, are hydrogen,lower-alkyl or lower-alkoxy.
 9. The compound according to claim 1,wherein R⁶ is hydrogen, methyl or methoxy.
 10. The compound according toclaim 1, wherein R⁷ is hydrogen or methyl.
 11. The compound according toclaim 1, wherein R⁸ is hydrogen.
 12. The compound according to claim 1,wherein R⁹ is hydrogen.
 13. The compound according to claim 1, whereinR¹⁴ is pyridinyl, quinolinyl or phenyl which is optionally substitutedwith 1 to 3 substituents selected from the group consisting of halogen,lower-alkyl, lower-alkoxy, lower-alkyl-SO₂, lower-alkoxy-carbonyl,cyano, fluoro-lower-alkyl, R¹⁵R¹⁶NC(O) and triazolyl, wherein R¹⁵ andR¹⁶ independently from each other are hydrogen or lower-alkyl.
 14. Thecompound according to claim 1, wherein R¹⁴ is phenyl, 2-methyl-phenyl,2-fluoro-phenyl, 2-chloro-phenyl, 3-fluoro-phenyl, 3-methyl-phenyl,quinolin-8-yl, 4-[1,2,4]-triazol-1-yl-phenyl, 2,4-difluoro-phenyl,pyridin-2-yl or 2,5-difluoro-phenyl.
 15. The compound according to claim1, wherein m is
 0. 16. The compound according to claim 1, wherein n is 0or 1 and R¹² and R¹³ are hydrogen.
 17. The compound according to claim1, wherein n is
 0. 18. The compound according to claim 1, selected fromthe group consisting of 2-(4-Benzyloxy-benzoylamino)-benzoic acid,2-[4-(4-Fluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(3,4-Dichloro-phenoxy)-benzoylamino]-benzoic acid,2-(4-p-Tolyloxy-benzoylamino)-benzoic acid,2-[4-(3-Methoxy-phenoxy)-benzoylamino]-benzoic acid,2-(4-o-Tolyloxy-benzoylamino)-benzoic acid,2-[4-(4-Methoxy-phenoxy)-benzoylamino]-benzoic acid,2-[4-(4-Chloro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(3,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(4-Methanesulfonyl-phenoxy)-benzoylamino]-benzoic acid,2-[4-[4-Methoxycarbonyl)phenoxy]benzoyl]aminobenzoic acid,2-[4-(3,5-Dichloro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(4-Cyano-phenoxy)-benzoylamino]-benzoic acid,2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(3-Chloro-phenoxy)-benzoylamino]-benzoic acid,2-(4-m-Tolyloxy-benzoylamino)-benzoic acid,2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoic acid,2-[4-(4-Trifluoromethyl-phenoxy)-benzoylamino]-benzoic acid,2-[4-(4-Carbamoyl-phenoxy)-benzoylamino]-benzoic acid,2-[4-(4-Dimethylaminomethyl-phenoxy)-benzoylamino]-benzoic acid,2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoic acid,2-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoic acid,2-[4-(Pyridin-3-yloxy)-benzoylamino]-benzoic acid,2-[4-(3,4-Dimethyl-phenoxy)-benzoylamino]-benzoic acid,2-[4-(2,3-Difluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid,2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid,2-(2-Methyl-4-phenoxy-benzoylamino)-benzoic acid,2-(2-Methoxy-4-phenoxy-benzoylamino)-benzoic acid,5-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid,4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid, and pharmaceuticallyacceptable salts and esters thereof.
 19. The compound according to claim1, selected from the group consisting of2-(4-o-Tolyloxy-benzoylamino)-benzoic acid,2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoic acid,2-(4-m-Tolyloxy-benzoylamino)-benzoic acid,2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoic acid,2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoic acid,2-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoic acid,2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid,2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid,4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid and pharmaceuticallyacceptable salts and esters thereof.
 20. The compound according to claim1, selected from the group consisting of2-[4-(3-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,2-[4-(2-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,2-[4-(2,4-Difluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,4-Chloro-5-fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and2-(4-Phenoxy-benzoylamino)-5-trifluoromethyl-benzoic acid, andpharmaceutically acceptable salts and esters thereof.
 21. A process forthe manufacture of compounds of formula (I) as defined in claim 1, whichprocess comprises a) reacting a compound of formula (II)

with a compound of formula (III),

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, mand n are as defined in any of claims 1-20 and R¹⁷ is OH, Cl, Br, or acarboxylic acid moiety to form an anhydride; or b) hydrolysis of acompound of formula (Ia)

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, m and nare as defined in any of claims 1-20 and R¹ is lower-alkyl.
 22. Apharmaceutical composition, comprising a therapeutically effecitveamount of a compound according to—claim 1 or a compound selected fromthe group consisting of:5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoicacid, 2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[(4-phenoxybenzoyl)amino]-benzoic acid,2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[[4-[(2,4-dichlorophenoxy) methyl]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic acid methyl ester,2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester, and 2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoicacid 1-methyl ethyl ester, and a pharmaceutically acceptable carrierand/or adjuvant.
 23. A method for the treatment and/or prevention ofdiseases which are modulated by HM74A agonists, comprising the step ofadministering a therapeutically effective amount of a compound accordingto—claim 1 or a compound selected from the group consisting of:5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoicacid, 2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[(4-phenoxybenzoyl)amino]-benzoic acid,2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methylester, 2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester,2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic acidmethyl ester,2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acidmethyl ester, 2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acidmethyl ester, and 2-[[4-[(2-chlorophenoxy) methyl]benzoyl]amino]-benzoicacid 1-methylethyl ester, to a human being or animal in need thereof.24. The method according to claim 23, wherein said disease is increasedlipid levels, increased cholesterol levels, atherosclerotic diseases,dyslipidemia, low HDL-cholesterol, hypertriglyceridemia, thrombosis,angina pectoris, peripheral vascular disease, stroke, diabetes,non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer'sdisease, Parkinson's disease, schizophrenia, impaired or improvablecognitive function, sepsis, inflammatory diseases, colitis, pancreatitisor cholestasisfibrosis of the liver.